Novel variants in PDE6A and PDE6B genes and its phenotypes in patients with retinitis pigmentosa in Chinese families

Abstract Background Retinitis pigmentosa (RP) is a genetically heterogeneous disease with 89 causative genes identified to date. However, only approximately 60% of RP cases genetically solved to date, predicating that many novel disease-causing variants are yet to be identified. The purpose of this study is to identify novel variants in PDE6A and PDE6B genes and present its phenotypes in patients with retinitis pigmentosa in Chinese families. Methods Five retinitis pigmentosa patients with PDE6A variants and three with PDE6B variants were identified through a hereditary eye disease enrichment panel (HEDEP), all patients’ medical and ophthalmic histories were collected, and ophthalmological examinations were performed, followed by an analysis of the possible causative variants. Sanger sequencing was used to verify the variants. Results We identified 20 variants in eight patients: 16 of them were identified in either PDE6A or PDE6B in a compound heterozygous state. Additional four heterozygous variants were identified in the genes ADGRA3, CA4, OPTN, RHO. Two novel genetic changes in PDE6A were identified (c.1246G > A and c.1747 T > A), three novel genetic changes in PDE6B were identified (c.401 T > C, c.2293G > C and c.1610-1612del), out of the novel identified variants one was most probably non-pathogenic (c.2293G > C), all other novel variants are pathogenic. Additional variant was identified in CA4 and RHO, which can cause ADRP (c.243G > A, c.688G > A). In addition, a novel variant in ADGRA3 was identified (c.921-1G > A). Conclusions This study reveals novel and known variants in PDE6A and PDE6B genes in Chinese families with autosomal recessive RP, and expands the clinical and genetic findings of photoreceptor-specific enzyme deficiencies.

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Novel Variants in Phosphodiesterase 6A and Phosphodiesterase 6B Genes and Its Phenotypes in Patients With Retinitis Pigmentosa in Chinese Families

10.21203/rs.3.rs-507306/v1 ◽

2021 ◽

Author(s):

Yuyu Li ◽

Ruyi Li ◽

Hehua Dai ◽

Genlin Li

Keyword(s):

Retinitis Pigmentosa ◽

Sanger Sequencing ◽

Autosomal Recessive ◽

Eye Disease ◽

Specific Enzyme ◽

Novel Mutations ◽

Chinese Families ◽

Novel Variants

Abstract Background: Retinitis pigmentosa (RP) is a genetically heterogeneous disease with 65 causative genes identified to date. However, only approximately 60% of RP cases genetically solved to date, predicating that many novel disease-causing variants are yet to be identified. The purpose of this study is to identify novel variants in phosphodiesterase 6A and phosphodiesterase 6B genes and present its phenotypes in patients with retinitis pigmentosa in Chinese families.Methods: Five retinitis pigmentosa patients with PDE6A variants and three with PDE6B variants were identified through a hereditary eye disease enrichment panel (HEDEP), all patients’ medical and ophthalmic histories were collected, and ophthalmological examinations were performed, then we analysed the possible causative variants. Sanger sequencing was used to verify the variants.Results: We identified 20 mutations sites in eight patients, two heterozygous variants were identified per patient of either PDE6A or PDE6B variants, others are from CA4, OPTN, RHO, ADGRA3 variants. We identified two novel variants in PDE6A: c.1246G > A;p.(Asp416Asn) and c.1747T > A;p.(Tyr583Asn). Three novel mutations in PDE6B: c.401T > C;p.(Leu134Pro), c.2293G > C;p.(Ala765Pro) and c.1610-1612del;p.(537-538del).CA4: c.243G > A;p.(Trp81*) and RHO: c.688G>A;p.(Val230Ile) are novel variants and maybe affecting the phenotype. Among them, c.401T > C;p.(Leu134Pro) variant in PDE6B is non- pathogenic; RHO: c.688G>A;p.(Val230Ile) is conflicting interpretations of pathogenicity;Other novel variants are all pathogenic.Conclusions: This study reveals novel and known variants in Chinese families with PDE6A and PDE6B mutations in autosomal recessive RP, expanding the clinical and genetic findings of photoreceptor-specific enzyme deficiencies.

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Identification of Novel Compound Heterozygous MYO15A Mutations in Two Chinese Families with Autosomal Recessive Nonsyndromic Hearing Loss

Neural Plasticity ◽

10.1155/2021/9957712 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Xiao-Hui Wang ◽

Le Xie ◽

Sen Chen ◽

Kai Xu ◽

Xue Bai ◽

...

Keyword(s):

Hearing Loss ◽

Autosomal Recessive ◽

Bioinformatics Analysis ◽

Compound Heterozygous ◽

Congenital Deafness ◽

Chinese Families ◽

Novel Variants ◽

Common Causes ◽

Compound Heterozygous Variants ◽

Generation Sequencing

Congenital deafness is one of the most common causes of disability in humans, and more than half of cases are caused by genetic factors. Mutations of the MYO15A gene are the third most common cause of hereditary hearing loss. Using next-generation sequencing combined with auditory tests, two novel compound heterozygous variants c.2802_2812del/c.5681T>C and c.5681T>C/c.6340G>A in the MYO15A gene were identified in probands from two irrelevant Chinese families. Auditory phenotypes of the probands are consistent with the previously reported for recessive variants in the MYO15A gene. The two novel variants, c.2802_2812del and c.5681T>C, were identified as deleterious mutations by bioinformatics analysis. Our findings extend the MYO15A gene mutation spectrum and provide more information for rapid and precise molecular diagnosis of congenital deafness.

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Three Novel Variants of CEP290 and CC2D2DA and a Link Between ZNF77 and SHH Signaling Pathway Are Found in Two Meckel-Gruber Syndrome Fetuses

Reproductive Sciences ◽

10.1007/s43032-021-00835-5 ◽

2022 ◽

Author(s):

Zhidan Hong ◽

Xuanyi He ◽

Fang Yu ◽

Huanyu Liu ◽

Xiaoli Zhang ◽

...

Keyword(s):

Autosomal Recessive ◽

Pathological Examination ◽

Compound Heterozygous ◽

Over Expression ◽

Pathogenic Variants ◽

Whole Exome ◽

The Family ◽

Novel Variants ◽

Novel Variant ◽

Missed Diagnosis

AbstractMeckel-Gruber syndrome (MKS) is a rare lethal autosomal recessive inherited disorder. Missed diagnosis might happen in clinical works due to an unclear genotype–phenotype correlation. We analyzed two families visiting our center; the parents are normal; each of the family aborted a fetus at 12WG. Following ultrasonography and pathological examination, both were diagnosed as MKS. Whole exome sequencing identified a compound heterozygous of two novel variants of CEP290 and a heterozygous of a novel variant of CC2D2A. Frameshift mutations in ZNF77 were also detected. Western blot analyzing whole-brain tissue showed that the expression of ZNF77, CC2D2A, and CEP290 was enhanced. HEK293T transfected with over-expression wildtype/mutated ZNF77 plasmid showed that SHH was increased in wildtype ZNF77 cells, while SHH and CC2D2A were increased in mutated ZNF77 cells. Our research provided two novel pathogenic variants of CEP290 and CC2D2A and suggested that ZNF77 might promote the expression of CC2D2A and regulate the amount of SHH.

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Autosomal Recessive Retinitis Pigmentosa Associated with Three Novel REEP6 Variants in Chinese Population

Genes ◽

10.3390/genes12040537 ◽

2021 ◽

Vol 12 (4) ◽

pp. 537

Author(s):

Lujia Zhang ◽

Ya Li ◽

Litao Qin ◽

Yu Wu ◽

Bo Lei

Keyword(s):

Retinitis Pigmentosa ◽

Autosomal Recessive ◽

Cultured Cells ◽

Missense Variant ◽

Chinese Families ◽

Targeted Next Generation Sequencing ◽

Novel Variants ◽

Next Generation Sequencing Ngs ◽

Computational Predictions

Retinitis pigmentosa 77 is caused by mutations of REEP6 (MIM: 609346), which encodes a protein for the development of photoreceptors. Our study was to identify disease-causing variants in three Chinese families using targeted next-generation sequencing (NGS). Multiple lines of computational predictions combined with in vitro cellular experiments were applied to evaluate the pathogenicity of the newly found variants. Three novel variants in REEP6, including one missense variant, c.268G>C, one frameshift variant, c.468delC, and one splicing variant, c.598+1G>C, were found, while c.268G>C was detected in all probands. The three variants were classified as likely pathogenic by the American College of Medical Genetics and Genomics (ACMG). REEP6 variant proteins c.268G>C and c.468delC in cultured cells destabilized the REEP6 protein and induced intracellular inclusions. Our data suggested that REEP6 c.268G>C may be a recurrent causative variant in Chinese autosomal recessive retinitis pigmentosa patients.

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A novel LOXHD1 variant in a Chinese couple with hearing loss

Journal of International Medical Research ◽

10.1177/0300060519884197 ◽

2019 ◽

Vol 47 (12) ◽

pp. 6082-6090 ◽

Cited By ~ 1

Author(s):

Chuan Zhang ◽

Shengju Hao ◽

Yali Liu ◽

Bingbo Zhou ◽

Furong Liu ◽

...

Keyword(s):

Hearing Loss ◽

Molecular Diagnosis ◽

Protein Function ◽

Mexican American ◽

Compound Heterozygous ◽

Congenital Hearing Loss ◽

Targeted Next Generation Sequencing ◽

Novel Variants ◽

Novel Variant ◽

Compound Heterozygous Variants

Objective To perform molecular diagnosis and genetic counseling in a young Chinese couple with congenital hearing loss. Methods Variant screening analysis was performed by PCR and direct Sanger sequencing or targeted next-generation sequencing of all known hearing loss genes. Novel variants were evaluated by PolyPhen2 and PROVEAN software tools to evaluate possible effects on protein function. Results We identified causative variants in the young couple: c.235delC (rs80338943)/c.299-300delAT (rs111033204) compound heterozygous variants of GJB2 in the husband and c.1828G>A (p.Glu610Lys, rs535637788)/c.2825-2827delAGA compound heterozygous variants of LOXHD1 in the wife. The LOXHD1 c.1828G>A variant has only previously been reported in a Mexican-American individual in the 1000 Genomes Project database. Using PolyPhen2 and PROVEAN, we speculated that the LOXHD1 variant c.1828G>A is potentially pathogenic. Conclusion We carried out molecular diagnosis in a young couple with congenital hearing loss, and identified different disease-causing genes in the two individuals. The LOXHD1 variant c.1828G>A present in the wife had not previously been reported in individuals with congenital hearing loss. We determined this to be a potential pathogenic variant, and a novel variant associated with hearing loss in a Chinese individual.

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Genetic Analysis of 28 Chinese Families With Tyrosinase-Positive Oculocutaneous Albinism

Frontiers in Genetics ◽

10.3389/fgene.2021.715437 ◽

2021 ◽

Vol 12 ◽

Author(s):

Linya Ma ◽

Jianjian Zhu ◽

Jing Wang ◽

Yazhou Huang ◽

Jibo Zhang ◽

...

Keyword(s):

Autosomal Recessive ◽

Oculocutaneous Albinism ◽

Type Ii ◽

Related Disorder ◽

Chinese Families ◽

Missense Variants ◽

Clinical Presentations ◽

Splicing Variants ◽

Novel Variants ◽

Generation Sequencing

BackgroundTyrosinase-positive oculocutaneous albinism (OCA, type II, OCA2) is an autosomal recessive genetic disease in which the biosynthesis of melanin decreases in the skin, hair, and eyes. OCA2 disease is caused by mutations in OCA2 gene. The gene product plays a role in regulating the pH of melanosomes. Up to now, hundreds of OCA2 mutations have been reported and novel variants are still being discovered.MethodsIn this study, we reviewed the records of OCA2 patients who had conducted albinism genetic testing, and then analyzed the clinical and genetic information of 28 OCA2 patients who had been genetically diagnosed by using Sanger sequencing and next-generation sequencing.ResultsIn this study, we reported 31 variants screened from 28 Chinese OCA2 families, and characterized the detailed molecular and clinical presentations. There were 12 novel variants among all detected variants, including 3 missense variants (p.G393V, p.T482A, and p.R720P), 4 frameshift variants (p.R53Gfs∗49, p.N279Kfs∗17, p.I469Lfs∗4, p.I655Nfs∗12), 2 splicing variants (c.1637-2A > G, c.1951 + 1G > C), 2 stopgain variants (p.L278X, p.W652X) and 1 insertion variants (p.P315LinsT). One potential cluster of missense variants was implicated indicating the important roles of the underlying domains in OCA2 pathogenesis.ConclusionOur results were beneficial for diagnosis and precision clinical management for OCA2-related disorder, and this study expanded the mutation spectrum of oculocutaneous albinism.

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Compound heterozygous variants in the ABCG8 gene in a Japanese girl with sitosterolemia

Human Genome Variation ◽

10.1038/s41439-020-00112-y ◽

2020 ◽

Vol 7 (1) ◽

Author(s):

Nobuhiro Hashimoto ◽

Sumito Dateki ◽

Eri Suzuki ◽

Takatoshi Tsuchihashi ◽

Aiko Isobe ◽

...

Keyword(s):

Plant Sterol ◽

Autosomal Recessive ◽

Elevated Serum ◽

Asian Population ◽

Autosomal Recessive Disorder ◽

Compound Heterozygous ◽

Heterozygous State ◽

Single Nucleotide ◽

Compound Heterozygous Variants ◽

Compound Heterozygous State

AbstractSitosterolemia is an autosomal recessive disorder that affects lipid metabolism and is characterized by elevated serum plant sterol levels, xanthomas, and accelerated atherosclerosis. In this study, we report a novel nonsense single-nucleotide variant, c.225G > A (p.Trp75*), and an East Asian population-specific missense multiple-nucleotide variant, c.1256_1257delTCinsAA (p.Ile419Lys), in the ABCG8 gene in a compound heterozygous state observed in a Japanese girl with sitosterolemia.

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